Opioid compounds are well established immunomodulators, and are known to influence resistance to a variety of infectious agents, including H1V. The alteration of cytokine and cytokine receptor expression is a particularly critical target for the opioids. It is our hypothesis that p-, K-, and 8-opioid agonists exhibit divergent influences on the generation of pro-inflammatory immune responses. The first specific aim is to study the impact of opioids and nociceptin on the expression of certain cytokines and cytokine receptors. These studies will emphasize an analysis of the expression of cytokines and receptors which are involved in promoting pro-inflammatory reactions. Given the particular significance of the chemokines, and their receptors, in controlling both pro-inflammatory responses, and resistance to HIV infection, we intend to give particular attention to an analysis of the regulation of these mediators and receptors. Our findings suggest that certain types of cellular activation alter opioid receptor expression, and that certain chemokines can directly activate leukocytes. We propose studies, as the second specific aim, to examine the capacity of chemokine receptor ligands to influence the expression of opioid and nociceptin receptors. Our emphasis will be on those chemokine receptors that serve as major or minor HW co-receptors. Our third specific aim is to study the basis for cross-talk between the opioid/nociceptin receptors and the chemokine receptors. We will examine the bidirectional regulation of opiold/nociceptin receptor and chemokine receptor function through the process of heterologous desensitization. Importantly, we intend to examine the functional consequences of opioid/nociceptin receptor-induced desensitization on those receptors which function as HIV co-receptors. These studies should enhance our understanding of the ability of certain drugs of abuse to control the immune response, and in particular, the interaction of the immune system with RN.